Pyridyl-2-phenylcycloalkenes and processes for their preparation



United States Patent 3,338,914 PYRIDYL-Z-PHENYLCYCLOALKENES ANDPROCESSES FOR THEIR PREPARATION Daniel Lednicer, Kalamazoo, Mich.,assignor to the Upjohn Company, Kalamazoo, Mich., a corporation ofDelaware No Drawing. Filed May 27, 1964, Ser. No. 370,672

19 Claims. (Cl. 260-297) This invention relates to novel polycyclicorganic compounds and is more particularly concerned with novelpyridyl-2-phenylbenzocycloalkenes and derivatives thereof, and acidaddition salts and quaternary ammonium salts thereof and with processesfor their preparation.

The novel compounds of the invention are selected from the classconsisting of:

(a) Compounds having the formula \cnn. (I)

wherein C,,H in which n is an integer from 1 to 6, inclusive, representsan alkylene radical and separates the carbon atom carrying the phenylradical from the carbon atom marked with an asterisk by from 1 to 2carbon atoms, inclusive, Py is selected from the class consisting of2-pyridyl, 3-pyridyl, and 4pyridyl, R represents at least onesubstituent selected from the class consisting of hydrogen, lower-alkyland halogen, and R represents at least one substituent selected from theclass consisting of hydrogen, lower-alkyl, lower-alkenyl,trifluoromethyl, lower alkoxy, lower-alkenyloxy, lower alkylenedioxy,cycloalkoxy from 4 to 7 carbon atoms, inclusive, halogen, andlower-alkylmercapto;

(b) The pharmacologically acceptable acid addition salts thereof; and

(c) The quaternary ammonium salts of the compounds of the above formulawherein the anion of the quaternary salt is that of a pharamacologicallyacceptable acid.

The alkylene radical -C,,H which forms part of the ring structure of thecompound (I) contains from 1 to 6 carbon atoms, inclusive, but not morethan 2 of the carbon atoms of the alkylene radical can be ring carbonatoms in the compound (I). In other words, the alkylene radical C,,H canhave either of the following structures:

'alkenyl group containing from 3 to 8 carbon atoms, in-

elusive, such as allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,and isomeric forms thereof. The term loWer-alkoxy means an alkoxy groupcontaining from 1 to 8 carbon atoms, inclusive, such as methoxy, ethoxy,

-propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, and isomericforms thereof. The term loweralkenyloxy means an alkenyloxy groupcontaining from 3 to 8 carbon atoms, inclusive, such as allyloxy,butenyl 3,338,914 Patented Aug. 29, 1967 oxy, pentenyloxy, hexenyloxy,heptenyloxy, octenyloxy, and isomeric forms thereof. The termcycloalkoxy from 4 to 7 carbon atoms, inclusive means cyclobutoxy,cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy. The term halogen isinclusive of fluorine, chlorine, bromine, and iodine. The termlower-alkylenedioxy means an alkylenedioxy group containing from 1 to 8carbon atoms, inclusive, such as methylenedioxy, ethylenedioxy,propylenedioxy, butylenedioxy, pentylenedioxy, hexylenedioxy,heptylenedioxy, octylenedioxy, and isomeric forms thereof. The termlower-alkylmercapto means an alkylmercapto group containing from 1 to 8carbon atoms, inclusive, such as methylmercapto, ethylmercapto, propylmercapto, butyhnercapto, pentylmercapto, hexylmercapto, heptylmercapto,octylmercapto, and isomeric forms thereof.

The acid addition salts of the invention comprise the salts of thecompounds having the Formula I with pharmacologically acceptable acidssuch as sulfuric, hydrochloric, nitric phosphoric, lactic, benzoic,methanesulfonic, p-toluenesulfonic, salicylic, acetic, propionic,maleic, tartaric, citric, cyclohexanesulfamic, succinic, nicotinic,ascorbic acids, and the like.

The quaternary ammonium salts of the invention are the salts obtained byreacting the free bases having the Formula I with quaternating agents,for example, lower- .alkyl halides, lower-alkenyl halides,di(loWer-a1kyl) sulfates, aralkyl halides, lower-alkyl arylsulfonates,and the like. The terms lower-alkyl and lower-alkenyl have the meaninghereinbefore defined. The term aralkyl means an aralkyl group containingfrom 7 to 13 carbon atoms, inclusive, such as benzyl, phenethyl,phenylpropyl, benzhydryl, and the like. The term lower-alkylarylsulfonates means the esters formed from lower-alkyl alcohols andarylsulfonic acids such as benzenesulfonic, toluenesulfonic,xylenesulfonic, and like acids. Examples of quaternary salts of thecompounds of Formula I are the methobromide, methiodide, ethobromide,propyl chloride, butyl bromide, octyl bromide, methyl methosulfate,ethyl ethosulfate, allyl chloride, allyl bromide, benzyl bromide,benzhydryl chloride, methyl toluenesulfonate, ethyl toluenesulfonate,and the like.

The novel compounds of the invention, including the free bases ofFormula I, the acid addition salts thereof, and the quaternary ammoniumsalts thereof, possess pharmacological activity. Illustratively, thecompounds of the invention are useful as antifertility agents in mammalsand birds, and as fungicidal agents.

The antifertility activity of the compounds of the invention isillustrated by that of the compounds 1-(3- pyridyl)- and1-(4-pyridyl)-2-phenyl-6-methoxy-3,4-dihydronaphthalene which exhibitoral antifertility activity at a dose of 0.5 mg./kg. when tested in ratsusing the method described by Duncan et al., Proc. Soc. Exp. Biol. Med.112, 439-442, 1963.

For purposes of administration to mammals, the novel compounds of the.invention can be combined with solid or liquid pharmaceutical carriersand formulated in the form of tablets, powder packets, capsules, andlike solid dosage forms, using starch and like excipients, or dissolvedor suspended in suitable solvents or vehicles, for oral or parenteraladministration.

The novel compounds of the invention are valuable for animal pestcontrol. For example, the compounds of the invention are formulated incombination with baits and/ or attractants and placed in feedingstations accessible to undesirable rodents and other small animalsincluding Canidae such as coyotes, foxes, wolves, jackals, and wild dogsand birds such as starlings, gulls, redwing blackbirds, pigeons, and thelike, thus reducing hazards to aviation by their presence on runways andin the vicinity of wherein R R and -C H have the significance abovedefined, with the appropriate pyridyl lithium compound, to obtain acarbinol having the formula:

wherein R R Py, and -C H have the significance hereinbefore defined; andsubsequently converting the carbinol (III) to the desired compound (I)by dehydration.

The reaction between the ketone (II) and the pyridyl lithium compound iscarried out advantageously in the presence of an inert solvent underanhydrous conditions. Suitable inert solvents include diisopropyl ether,diisobntyl ether, dibutyl ether, tetrahydrof-uran, and the like.Preferably, the reaction is carried out at temperatures within the rangeof about -80 C. to about 0 C. The reaction time varies within widelimits according to the temperature at which the reaction is conducted.Generally speaking, it is desirable to employ a reaction time of theorder of 30 minutes to 2 hours.

The carbinol (III) can be isolated from the reaction mixture byconventional procedures, for example, by de composing the reactionmixture with water, ammonium chloride, and the like, followed byseparation of the organic layer and removal of solvent therefrom or byextracting the organic layer with aqueous acid, making the acid extractbasic, and isolating the product which separates.

The carbinol (III) can be converted to the desired compound (I) bydehydration. The dehydration can be eifected by heating the compound(III) in an inert solvent such as benzene, toluene, xylene, and thelike, which forms an azeotrope with water, in the presence of a strongacid such as hydrochloric, sulfuric, p-toluenesulfonic acids, and thelike. The water which is formed in the dehydration is removed from thereaction mixture azeotropically. There is thereby obtained a solution ofthe desired compound (I) from which the latter can be isolated byevaporation or other conventional procedures.

The carbinols having the Formula III in addition to being useful asintermediates in the preparation of the corresponding compounds (I) alsopossess pharmacological activity. Illustratively, the compounds of theFormula III, which can exist in either the form of the free bases or inthe form of acid addition and quaternary ammonium salts, are useful asantifertility agents in mammals and birds, and as fungicidal agents.

The ketones having the Formula II which are employed as startingmaterials in the above process can be prepared by methods known in theart. For example, the compounds having the Formula II which arel-indanones, i.e., wherein C H represents methylene or alkyl- .4substituted methylene, can be prepared by the procedures described inBelgian Patent 612,512. The compounds having the Formula II which are1,2,3,4-tetrahydro-1- naphthalenones (a-tetralones), i.e., wherein--C,,H represents ethylene or alkyl-substituted ethylene, can beprepared by the procedures described in French Patent 1,343,580.

Said 1,2,3,4-tetrahydro-1-naphthalenones wherein represents ethylene canalso be prepared by a variation of the process described in theaforesaid French patent,

which variation is illustrated by the following reaction scheme:

(VIII) COzH In the above formulae R and R have the significancehereinbefore defined, and R represents lower-alkyl as hereinbeforedefined or aryl from 6 to 12 carbon atoms, inclusive, such as phenyl,tolyl, xylyl, naphthyl, biphenylyl, and the like.

In the above reaction sequence the appropriately substitutedphenylacetic acid (IV) is reduced to the corresponding phenethyl alcohol(V) using reducing agents well-known in the art for the reduction ofcarboxylic acids to primary alcohols. Illustrative of the reducingagents which can be employed are lithium aluminum hydride,dibutylaluminum hydride, and the like. The phenethyl alcohol (V) soobtained is then converted to the corresponding sulfonate (VI) byreaction with the appropriate hydrocarbon sulfonyl halide RSO Halwherein R is as hereinbefore defined and Hal represents halogen,preferably chlorine or bromine. The sulfonate (VI) is then condensedwith the appropriately substituted benzyl cyanide-(VII) to form thecorresponding 2,4-diphenylbutyronitrile (VIII). The condensation isadvantageously carried out by bringing the reactants together in aninert solvent in the presence of a base such as sodium hydride, lithiumhydride, potassium hydride, and the like. Inert solvents which can beused in the condensation include benzene, toluene, xylene, diethylether, dimethylformamide, tetrahydrofuran, dioxane, and the like. Thebutyronitrile (VIII) so obtained is then hydrolyzed to the correspondingacid (IX) using'procedures conventional in the art for the hydrolysis ofnitriles, for example, by heating under reflux in the presence ofaqueous mineral acid such as sulfuric acid, until hydrolysis issubstantially complete. The acid (IX) is then cyclized to the requireda-tetralone (X) in the presence of a Lewis acid, using the generalprocedure described by Fieser and Hershberg, J. Am. Chem. Soc. 61, 1272,1939. The term Lewis acid is well known in the art and is defined byFieser and Fieser, Organic Chemistry, third edition, p. 138 (Reinhold,1956). Examples of such compounds are hydrogen fluoride, borontrifluoride, arsenic trifluoride, phosphorus pentachloride, phosphoruspentaflu-oride, titanium tetrafluoride, concentrated sulfuric acid,polyphosphoric acid, and the like.

Representative of the l-indanones and u-tetralones of the Formula IIwhich can be employed in the process of the invention are: 2-p-tolyl-,2-phenyl-6-methoxy-, 2-phenyl-5-methoxy-,

2- (p-chlorophenyl 2-(p-fluorophenyl)-, 3-methyl-2-phenyl-, -p py (py2-phenyl-5-methylmercapto-, 2-phenyl-5-allyloxy-,Z-phenyl-5-trifluoromethyl-, Z-phenyl-5,6-methylenedioxy-,2-phenyl-5,6-dichloro-, and 2-phenyl-6-(1,3-dimethylbutyl)-1-indanone;and 1 2-phenyl-7-amyl-, 2-phenyl-6-bromo-, 2-phenyl-8-chloro-5-methoxy-,2-phenyl-6-allyl-7-methoxy-, 2-phenyl-7-methylmercapto-,Z-phenyl-6-trifluoromethyl-, 2-pheny1-3-methyl-, 2-phenyl'3-ethyl-,2-(2-bromophenyl)-,

2-( 3 -chlorophenyl) 2-p-tolyl-, and

2-phenyl-6-allyloxy-1,2,3,4 tetrahydro 1 naphthalenone.

The acid addition salts of the compounds of the invention having theFormulas I and III can be prepared by methods well known in the art. Forexample, the acid addition salts of the invention can be prepared byreacting a free base having the Formula -I or III with apharmacologically acceptable acid, as hereinbefore exemplified, in thepresence of an inert solvent such as methanol, ethanol, diethyl ether,ethyl acetate, and the like.

The quarternary ammonium salts of the invention can be prepared byreacting a free base of the Formula I or III with a quarternating agent,for example, an alkyl halide such as methyl iodide, ethyl chloride,isopropyl bromide, and the like, an alkenyl halide such as allylchloridefallylbromide, and the like, a dialkyl sulfate such as dimethylsulfate, diethyl sulfate, and the like, an aralkyl halide such as benzylbromide, benzhydryl chloride, phenethyl bromide, and the like, or analkyl arylsulfonate 'such as methyl p-toluenesulfonate, and the like.Preferably the reaction is eifected by bringing the reactants togetherin the presence of an inert solvent such as acetonitrile, acetone,methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide, and thelike. Generally speaking, the desired quaternary salt separates readilyfrom the reaction mixture and can be isolated by filtration.Purification of the quaternary salt can be effected by conventionalmethods, for example, by recrystallization.

'The anion of the quaternary ammonium salt obtained as described abovecan be exchanged for any other desired anion, e.g., the anions of thevarious acids enumerated previously, by conventional procedures. Forexample, any of the quaternary ammonium salts of the invention can beconverted to the corresponding quaternary ammonium hydroxide,illustratively by treating with silver oxide, and the hydroxide soobtained is reacted with the appropriate acid to obtain the desiredquaternary ammonium salt.

The following preparation and examples illustrate the best methodcontemplated by the inventor for carrying out his invention, but are notto be construed as limiting the scope thereof.

PREPARATION 2-phenyl-6-meth0xy-1,2,3,4-tetrahydro-1-naph thalenone Asolution of g. of m-methoxyphenylacetic acid in 600 ml. of diethyl etherwas added to a mechanically stirred suspension of 34 g. of lithiumaluminum hydride in 30 ml. of diethyl ether at such a rate as to producea vigorous reflux. Following this, the mixture was heated under refluxfor 30 minutes, and then cooled in an ice bath. The reaction mixture wasthen cautiously decomposed with 50 ml. of water. There was then added inturn 500 ml. of saturated aqueous ammonium chloride solution and 300 ml.of 2.5 N hydrochloric acid. The organic layer was separated, washedtwice with water, once with saturated aqueous sodium chloride solution,and dried by percolation through anhydrous sodium sulfate.

The oil (91.1 g.) which remained when the solvent was removed undervacuum was distilled through a short Vigreux column. There was obtained84.5. g. of m-methoxyphenethyl alcohol having a boiling point of 99-102C. at a pressure of 1 mm. of mercury.

A solution of 15.2 g. of the m-methoxyphenethyl aloohol in 75 ml. ofpyridine was cooled in an ice-methanol bath. Over a period of 10 minutes15.2 g. of methanesulfonyl chloride was added to the solution withstirring. Following additional stirring for l hour in the cold, themixture was diluted to 600 ml. with ice and water. The precipitated oilwas extracted "with diethyl ether, and the ethereal solution was in turnwashed with water, 2.5 N hydrochloric acid, water, and saturated aqueoussodium chloride solution. The solvent was removed to afford 22.27 g.. ofm-methoxyphenethyl me'thanesulfonate as a viscous oil.

To an ice cooled, well stirred solution of 11.7 g. of phenylacetonitrilein 50 ml. of dry dimethylformamide and 25 ml. of dry toluene there wasadded 4.50 g. of sodium hydride (53% suspension in mineral oil).Following stirring for 1 hour under nitrogen, there was added 22.27 g.of m-methoxyphenethyl methanesulfonate (prepared as described above) in30 ml. of toluene. The mixture was then allowed to stir overnight atabout 25 C. The bulk of the solvent was removed in vacuo, and water anddiethyl ether were added. The organic layer was washed in turn withwater and saturated aqueous sodium chloride solution, and dried bypercolation through anhydrous sodium sulfate. The oil which remainedwhen the solvent was removed was distilled at a pressure of 1-2 mm. ofmercury through a Vigreaux column. There was obtained 6.03 g. offorerun, B.P. 52-170 C. (mainly 54-64 C.) and 18.79 grof 4-(m- 7methoxyphenyl)-2-phenylbutyronitrile having a boiling point of 170-190C.

A mixture of 18.79 g. of 4-(m-methoxyphenyl)-2- phenylbutyronitrile(prepared as described above) and 20 g. of potassium hydroxide in 200ml. of ethylene glycol was heated overnight at reflux. The resultingsolution was allowed to cool, diluted with 600 ml. of water, andextracted once with diethyl ether. This extract was discarded. Theaqueous layer was then acidified with concentrated hydrochloric acid andextracted well with diethyl ether. These last extracts were washed inturn with water and saturated aqueous sodium chloride solution, anddried by percolation through anhydrous sodium sulfate. The solution wastaken to dryness in vacuo, the residue dissolved in dry benzene, and thesolution again taken to dryness. 4-(m-methoxyphenyl)-2-phenylbutyricacid (16.29 g.) was obtained as a clear amorphous gum.

A solution of 16.29 g. of 4-(m-methoxyphenyl)-2- phenylbutyric acid soobtained and 12.7 g. of phosphorus pentachloride in 250 ml. of drybenzene was heated under reflux for 1 hour. The solution was then cooledin ice and 7.15 ml. of stannic chloride was added with stirring.Following 2.5 hours stirring at about 25 C. the twophase mixture waspoured into 250 ml. of 2.5 Nhydrochloric acid. Following 0.5 hourstirring, the organic layer was separated, and washed in turn with 2.5 Nhydrochloric acid, water, saturated aqueous sodium bicarbonate solution,water, and saturated aqueous sodium chloride solution. A crystallinesolid remained when the solution was taken to dryness. This wasrecrystallized from methanol to afford 11.34 g. of 2-phenyl-6-methoxy-1,2,3,4-tetrahydro-1-naphtha1enone, M.P. 113-116 C.; mixed M.P. withauthentic material, 113.5117 C.

Similarly, using the above procedure but replacing mmethoxyphenylaceticacid by 4-chlorophenylacetic acid, 3-bromophenylacetic acid,3,4-methylenedioxyphenylacetic acid, 4-trifluoromethylphenylacetic acid,3-chloro- 4-methylphenylacetic acid, 4-cyclobutoxyphenylacetic acid and4-allylphenylacetic acid, there are obtained 7- chloro, 6-bromo-,6,7-methylenedioxy-, 7-trifluoromethyl-, 6-chloro-7-metbyl-,7-cyc1obutoxy-, and 7-allyl-2- phenyl 1,2,3,4tetrahydro-l-naphthalenone,respectively. Similarly, using the above procedure, but replacingphenylacetonitrile by p-fluorophenylacetonitrile,m-chlorophenylacetonitrile, p-methylphenylacetonitrile,m-ethylphenylacetonitrile, and o-propylpheny1acetonitrile, there areobtained 2-p-fluorophenyl-, 2-m-chloropheny1-, 2-ptoly1-,2-m-ethylphenyl-, and 2-o-propylphenyl-fi-methoxy-1,2,3,4-tetrahydro-l-naphthalenone, respectively.

EXAMPLE 1 A. 1-hydr0xy-6-meth0xy-2-phenyl-1-(Z pyria'yl) -1,2,3 ,4..tetrahydronaph thalene Over a period of 20 minutes a solution of 3.16 g.of 2-bromopyridine in 30 ml. of diethyl ether was added with stirring to26.5 ml. of freshly prepared 0.75 M butyl lithium in diethyl ether,while cooling the mixture in an ice-methanol bath. After an additional20 minutes stirring, a solution of 5.28 g. of 2-phenyl-6-methoxy-l,2,3,4-tetrahydro-1-naphthalenone in 75 ml. of tetrahydrofuran was added overa period of 30 minutes with continued cooling. The mixture was thenstirred for 1 hour and decomposed with 25 ml. of saturated aqueousammonium chloride solution. The organic layer was separated, washed withwater, and extracted with 250 ml. of 2.5 N hydrochloric acid. Theprecipitate which was obtained when the extract was made 'basic wasrecrystallized three times from aqueous methanol to yield 1.30 g. of1-hydroxy-6-methoxy-2-phenyl-1-(2-pyridyl)-1,2,3,4-tetrahydronaphthalene having a melting point of 127 to 129.5 C.

Analysis.-Calcd. for C H NO C, 79.73; H, 6.39'; N, 4.23. Found: C,79.80; H, 6.66; N, 4.09.

8 B. 1- (Z-pyridyl) -2-phenyl-6-meth0xy- 3,4-dihydronaphthalene Amixture of 2.58 g. of 1-hydroxy-6-metl1oxy-2-phenyl-1-(2-pyridyl)-1,2,3,4-tetrahydronaphthalene and 1.70 g. ofp-toluenesulfonic acid in 100 ml. of toluene was heated at reflux undera Dean-Stark trap for 5 hours. The solvent was then evaporated undervacuum and the residue was dissolved in methylene chloride. Thissolution was washed with aqueous potassium carbonate solution andevaporated to dryness. The residual solid was recrystallized frommethanol to yield 2.0 g. of1-(2-pyridyl)-2-phenyl-6-methoxy-3,4-dihydronaphthalene having a meltingpoint of 143 to 145 C.

Analysis.Calc'd. for C H NO: C, 84.31; H, 6.11; N, 4.47. Found: C,84.19; H, 6.18; N, 4.53.

EXAMPLE 2 A. 1 -hydr0xy-6-m'eth0xy-2-phenyl-1-(4-pyridyl)1,2,3,4-tetrahydr0naphthalene To 23.5 ml. of 0.845 M butyl lithium indiethyl ether cooled in a solid carbon dioxide-acetone bath under astream of nitrogen there was added, over 35 minutes, 3.16 g. of4-bromopyridine in 60 ml. of diethyl ether. A solution of 5.0 g. of2-phenyl-6-methoxy-l,2,3,4-tetrahydrol-naphthalenone in 75 m1. oftetrahydrofuran was added with stirring to the resulting yellow graysuspension over 40 minutes. Following an additional minutes stirring,

' the mixture was allowed to come to ice bath temperature over 1 hour.Saturated aqueous ammonium chloride solution (25 ml.) was then added.The organic layer was washed with Water and saturated aqueous sodiumchloride solution, and taken to dryness on a rotary evaporator. Theresidue was dissolved in diethyl ether and this solution was extractedwith three -ml. portions of 2.5 N hydrochloric acid. The solid which wasobtained when the solution was made basic was collected by filtrationand recrystallized from aqueous methanol. There was obtained 2.56 g. of1-hydroxy-6-methoxy-2-phenyl-1-(4-pyridyl)-1,2,3,4-tetrahydronaphthalene having a melting point of 183 to 185 C.

One further recrystallization gave an analytical sample, melting point182 to 185 C.

Analysis.-Cal :d. for C H NO C, 79.73; H, 6.39; N, 4.23. Found: C,79.65; H, 6.59; N, 4.57.

B. 1- (4-pyridyl) -2-phenyl-6-methoxy- 3,4-dihydronaphthalen'e Asolution of 8.0 g. of 1-hydroxy-6-methoxy-2-phenyl-1-(4-pyridyl)-1,2,3,4-tetrahydronaphthalene and 3.3 g. ofp-toluenesulfonic acid in 200 ml. of toluene was heated at reflux undera Dean-Stark trap for 4 hours. The product was isolated in the samemanner as the 2-pyridyl compound of Example 1, part B, andrecrystallized from methanol to give 3.75 g. of 1-(4-pyridyl)-2-phenyl6methoxy-3,4- dihydronaphthalene having a melting point of to 133.5 C.

An analytical sample melting at 134 to 136.5 C. was obtained by furtherrecrystallization from methanol.

Analysis.-Calcd. for C H NO: C, 84.31; H, 6.11. Found: C, 84.12; H,6.39.

EXAMPLE 3 A. 1-hydroxy-6-meth0xy-2-phenyl-I- (3-pyridyl)1,2,3,4-tetrahydronaphthalene Using the procedure described in Example1, part A, but replacing 2-bromopyridine by 3-bromopyridine, there wasobtained 1 hydroxy 6 methoxy-2-phenyl-1-(3-pyridyl)-1,2,3,4-tetrahydronaphthalene in the form of an amorphous solid.

B. I-(S-pyridyl)-2-phenyl-6-methoxy- 3,4-dihydronaphthalene Using theprocedure described in Example 1, part B, 4.14 g. of1-hydroxy-6-methoxy-2-phenyl-1-(3-pyridyl)- 91,2,3,4-tetrahydronaphtha1enewas dehydrated to yield 2.82 g. of1-(3-pyridyl)-2-phenyl-6-methoxy-3,4-dihydronaphthalene in the form of acrystalline solid having a melting point of 136 to 139 C. afterrecrystallization from aqueous methanol. An analytical sample having amelting point of 137 to 140 C. was obtained by further recrystallizationfrom aqueous methanol.

Analysis.--Calcd. for C H NO: C, 84.31; H, 6.11; N, 4.47. Found: C,83.50; H, 6.13; N, 4.53.

EXAMPLE 4 A. 1-hydr0xy-2-phenyl-1-(Z-pyridyl)1,2,3,4-tetrahydrnaphthalene Using the procedure described in Example 1,part A, but replacing 2phenyl-6-rnethoxy-1,2,3,4-tetrahydro-l-naphthalenone by2-phenyl-1,2,3,4-tetrahydro-l-naphthalenone, there is obtained1-hydr0xy-2-phenyl-1- (2-pyridyl -1,2,3 ,4- tetrahydronaphthalene.

B. Z-phenyl-I (Z-pyridyl) -3,4-dihydr0naphthalene Using the proceduredescribed in Example 1, part B, but replacing 1 hydroxy-6-methoxy-2-phenyl-1-(2-pyridyl)- 1,2,3,4 tetrahydr'onaphthalene by1-hydroxy-2-phenyl-1- (2-pyridyl)-1,2,3,4-tetrahydronaphthalene, thereis obtained 2-phenyl-1- (2-pyridyl) -3 ,4-dihydronaphthalene.

Similarly, using the procedure described in Example 1, parts A and B,but replacing 2-phenyl-6-methoxy-1,2,3,4- tetrahydro-l-naphthalenone bythe appropriate 1,2,33,4- tetrahydro-l-naphthalenone, there are obtainedother 3,4- dihydronaphthalenes of the invention and the correspondingcarbinols. Representative of the compounds so prepared are:

"2-p-fluorophenyl-6-methoxy-1-(2-pyridy1) -3 ,4-dihydronaphthalene andthe corresponding carbinols.

The corresponding 1-(3-pyridyl) and 1-(4-pyridyl) isomers of the abovecompounds can be prepared by employing 3-bromopyridine and4-bromopyridine, respectively, in place of 2-bromopyridine in theprocedure of Example 1, part A.

EXAMPLE 5 I A. 3-hydroxy-2-phenyl-3-(Z-pyridyl)-5-methoxyindane Usingthe procedure of Example 1, part A, but replacing 2 phenyl6-methoxy-1,2,3,4-tetrahydro-1-naphthalenone by2-pheny1-6-methoxy-l-indanone, there is obtained 3-hydroxy-2-phenyl-3(2-pyridyl -5-methoxyindane.

B. 2 -phenyl-3- (Z-pyridyl)-5-meth0xyindene Using the procedure ofExample 1, part B, but replacing 1hydroXy-6-methoXy-2-phenyl-1-(2-pyridy1)-1,2,3,4- tetrahydronaphthaleneby 3 hydroxy-2-phenyl-3-(2-pyridyl) -5-met-hoxyindane, there is obtained2-pheny1-3-(2- pyridyl)-5-methoxyindene.

Similarly, using the procedure described in Example 1, parts A and B,but replacing 2-phenyl-6-methoxy-1,2,3,4-

- tetrahydro- 1 -naphthalenone by the appropriate l-indanone, there areobtained other indenes of the invention and the corresponding carbinols.Representative of the. compounds so prepared are:

2-p-tolyl-, 2-phenyl-6-methoXy-, 2- (p-chlorophenyl)-, 2-(p-fluorophenyl) 1-methy1-2-phenyl-, 1-propyl-2- (p-toly1)-,2-phenyl-6-methylmercapt0-, 2-phenyl-6-al1yloxy-,2-phenyl-6-trifluoromethyl-, 2-phenyl-5,6-methylenedioXy-,2-phenyl-5,6-dichloro-, and 2-phenyl-5- 1,3-dimethylbutyl -3-(2-pyridy1)indene and the corresponding carbinols.

The corresponding 3-(3-pyridyl) and 3-(4-pyridyl) isomers of the abovecompounds can be prepared by employing S-bromopyridine and4-bromopyridine, respectively, in place of 2-bromopyridine in theprocedure of Example 1, part A.

EXAMPLE 6 I- (Z-pyridyl) -2-phenyl-6-meth0xy-3,4-dihydron'wphthalenemethiodide A solution of 1.0 g. of1-(2-pyridyl)-2-phenyl-6-methoxy-3,4-dihydronaphthalene in 25 ml. ofmethyl iodide was allowed to stand at about 25 C. Within 15 minutessolid started to separate. At the end of 17 hours the excess reagent wasremoved on a rotary evaporator and the residue was recrystallized fromacetonitrile. There was obtained 1.05 g. of 1-(2-pyridyl)-2-phenyl-6-rneth0Xy-3,4,- dihydronaphthalene methiodide having amelting point of 224 to 226 C.

Analysis.Calcd. for C H INO: C, 60.67; H, 4.87; I, 27.87. Found: C,60.79; H, 5.61; I, 27.90.

EXAMPLE 7 1-(3-pyridyl)-2-phenyl-6-meth0xy-3,4-dihydronaphthalenemethiodide Using the procedure described in Example 6, but replacing 1(2 pyridyl)-2-phenyl-6-methoxy-3,4-dihydronaphthalene by1-(3-pyridyl)-2-phenyl-6-methoXy-3,4-dihydronaphthalene, there wasobtained 1-(3-pyridyl)-2- phenyl-6-methoxy-3,4-dihydronaphthalenemethiodide in the form of a crystalline solid having a melting point of238 to 241.5 C.

Analysis.Calcd. for C H INO: C, 60.67; H, 4.87. Found: C, 60.56; H,5.18. 1

Similarly, using the procedure described in Example 6, but replacing 1(2 pyridyl)-2-phenyl-6-methoxy-3,4-dihydronaphthalene by1-(4-pyridyl)-2-phenyl-6-methoxy- 3,4-dihydronaphthalene, there wasobtained l-(4-pyridyl)- 2-pheny1- 6 methoxy-3,4-dihydronaphthalenemethiodide in the form of a crystalline solid having a melting point of285 to 286C.

Analysis.-Calcd. for C H INO: C, 60.67; H, 4.87. Found: C, 60.85; H,5.20.

Similarly, using the above procedure, other l-(p-yridyD-3,4-dihydronaphthalenes and 3-(pyridyl)inde'nes oif the invention,illustratively those named in Examples 4 and 5, are converted to thecorresponding methiodides.

EXAMPLE 8 1- (Z-pyridyl) -2-phenyl 6-methoxy-3,4-dihydronaphthaleneethobromide Using the procedure described in Example 6, but replacingmethyl iodide by ethyl bromide, there is obtained 1-(2-pyridyl)-2-phenyl-6-\meth0xy-3,4 dihyd-ronaphthalene ethobromide.

Similarly, by reacting other alky l halides with 1-(2-pyridyl)-2-phenyl-6-methoxy-3,4-dihydronaphthalene accor-ding to theprocedure of Example 6, there are obtained other quaternary ammoniumsalts of the invention.

EXAMPLE 9 1-(4-pyridyl) -2-phenyl-6-meth0xy-3,4-dihydr0naphthalenem-ethochloria'e A solution of 1 g. of 1-(4-pyridyl)-2-phenyl-6-methoxy-3,4-dihydronaphthalene methiodide in dimethylformamide is shaken with aslight excess of silver oxide until the precipitation of silver iodideis complete. The resulting mixture is filtered and the filtratecontain-ing the corresponding quaternary ammonium hydroxide isneutralized by the addition of aqueous hydrochloric acid. The resultingmixture is evaporated to dryness to obtain 1-(4-pyridyl)-2phenyl-6-methoxy 3,4 dihydronaphthalene methochloride.

Similarly, using the above procedure but replacing hydrochloric acid byother acids such as sulfuric acid, hydrobromic acid, phosphoric acid,acetic acid, methanesulfoni'c acid, and the like, there are obtained thecorresponding quaternary ammonium salts. I

In like manner, using the above procedure, the anion of any of thequaternary ammonium salts of the invention can be exchanged by any otherdesired anion by forming the corresponding quaternary ammonium hydroxideand reacting the latter with the appropriate acid.

EXAMPLE 1- (Z-pyridyl) -2-phenyl-6-meth0xy-3,4-dihydronaphthalene hydrobromide To a solution of 1 g. of1-(Z-pyridyl)-2-phenyl-6-methoxy-3,4-'dihydronaphthalene in 100 ml. ofether is added dropwise with stirring a slight excess of a 0.1 Nethereal solution of hydrogen bromide. The solid which separates isisolated by filtration, washed with diethyl ether, and dried. There isthus obtained 1-(2-pyridyl)-2-phenyl 6- methoxy-3,4-dihydronaphthalenehydrobromide.

In like manner, employing any of the free bases of the invention and theappropriate acid, there are obtained the corresponding acid additionsalts. lllustratively, using procedures analogous to that describedabove, the free bases of Examples 1 through 5 are converted to theiracid addition salts with sulfuric, nitric, phosphoric, lactic, 'benzoic,methanesulfonic, p-toiluenesulfonic, salicylic, acetic, propionic,malic, tartaric, citric, cyclohexanesulfamic, succinic, nicotinic, andascorbic acids.

I claim:

1. A compound selected from the class consisting of (a) compounds havingthe formula wherein C,,H in which n is an integer from 1 to 6,inclusive, represents an alkylene radical and separates the carbon atomcarrying the phenyl radical from the carbon atom marked with an asteriskby from 1 to 2 carbon atoms, inclusive, Py is selected from the classconsisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl, R represents at leastone substituent selected from the class consisting of hydrogen,lower-alkyl and halogen, and R represents at least one substituentselected from the class consisting of hydrogen, loweralkyl,lower-allcenyl, trifluoromethyl, lower-alkoxy, lower-alkenyloxy,lower-alkylenedioxy, cycloalkoxy from 4 to 7 carbon atoms, inclusive,halogen and lower-a lkylmercapto;

('b) the pharmacologically acceptable acid addition salts thereof; and

(c) the quaternary ammonium salts of the compounds of the above formulawherein the anion of the quaternary salt is that of a pharmacologicallyacceptable acid. 2. An indene selected from the class consisting of (a)compounds having the formula of the above formula wherein the anion ofthe quaternary salt is that of a pharmacologically acceptable acid. 3. Adihydronaphthalene selected from the class consisting of (a) compoundshaving the formula wherein Py is selected from the class consisting of2-pyridyl, 3-pyridyl, and 4-pyridyl, R represents at least onesu-bstituent selected from the class consisting of hydrogen, lower-alkyland halogen, and R represents at least one substituent selected from theclass consisting of hydrogen, lower-alkyl, lower-alkenyl,trifluoromethyl, lower-alkoxy, lower-alkenyloxy, lower-alkylenedioxy,cycloalkoxy from 4 to 7 carbon atoms, inclusive, halogen, andloWer-alkylmercapto; (b) the pharmacologically acceptable acid additionsalts thereof; and (c) the quaternary ammonium salts of the compounds ofthe above formula wherein the anion of the quaternary salt is that of apharmacologically acceptable acid. 4. A compound selected from the classconsisting of 1 (2 pyridyl) 2 phenyl 6 methoxy 3,4 dihydronaphthaleneand the salts thereof with pharmacologically acceptable acids.

5. 1 (2 pyridyl) 2 phenyl 6 methoxy 3,4-dihydronaphthalene.

6. A compound selected from the class consisting of 1 (4 pyridyl) 2phenyl 6 methoxy 3,4 dihydronaph-thalene and the salts thereof withpharmacologically acceptable acids.

7. 1 (4 pyridyl) 2 phenyl 6 methoxy 3,4 dihydronaphthalene.

8. A compound selected from the class con-sisting of l (3 pyridyl) 2phenyl 6 methoxy 3,4-dihydronaphthalene and the salts thereof withpharmacologically acceptable acids.

9. 1 (3 pyridyl) 2 phenyl 6 methoxy 3,4 dihydronaphthalene.

10. 1 (2 pyridyl) 2 phenyl 6 methoxy 3,4- dihydronaphthalene methiodide.

11. 1 (3 pyridyl) 2 phenyl 6 methoxy 3,4 dihydronaphthalene methiodide.

12. 1 (4 pyridyl) 2 phenyl 6 methoxy 3,4 dihydronaphthalene methiodide.

13 13. A compound selected from the class consisting of (a) compoundshaving the formula 14 least one substituent selected from the classconsisting of hydrogen, loWer-alkyl and halogen, and R represents atleast one substituent selected from the class Py consisting of hydrogen,loWer-alkyl, lower-alkenyl,

R1 5 trifiuoromethyl, lower-alkoxy, lower-alkenyloxy, wer-alkylenedioxy,cycloalkoxy from 4 to 7 carbon atoms, inclusive, halogen, andlower-alkylmercapto; zzn (b) the pharmacologically acceptable acidaddition wherein C H in which n is an integer from 1 Salts thereof; andto 6, inclusive, represents an alkylene radical and sep- 10 thequaternary ammonium Salts of the compounds mates the carbon atomcarrying the phenyl radica1 of the above formula wherein the anion ofthe quafrom the carbon atom marked with an asterisk by tefflaly Salt isthat of a Pharmacologicany acceptable from 1 to 2 carbon atoms,inclusive, Py is selected acldfrom the class consisting of 2-pyridyl,3-pyridyl, and 1 Y Y 6 y' 'p y -py 4-py-ridyl, R represents at least onesubstituent se- 1:23:4'tetrahydronaphthalenelected from the classconsisting of hydrogen, lower- 1 Y Y 6 y- -p y -PY YD- alkyl andhalogen, and R represents at least one sub-152,3,4'tetfahydmnaphthalenestituent selected from the class consistingof hydro- 1 Y Y 6 y' 'p y -p y gen, lower-alkyl, lower-alkenyl,trifiuorornethyl, low- 13,3,4"tetfahydronaphthaleneepalkoxy,lowepalkenyloxy, lower alkylenedioxy 20 19. A process for thepreparation of a compound havcycloalkoxy from 4 to 7 carbon atoms,inclusive, halogen, and lower-alkylmercapto;

-(b) the pharmacologically acceptable acid addition salts thereof; and

ing the formula (c) the quaternary ammonium salts of the compounds ofthe above formula wherein the anion of the quaternary salt is that of apharmacologicailly acceptable R, acid. 14. An indane selected from theclass consisting of (a) compounds having the formula Cu Zn Py OH R1wherein C,,H in which n is an integer from 1 to 6, inclusive, representsan alkylene radical and R2 Q separates the carbon atom carrying thephenyl radical from the carbon atom marked with an asterisk by from 1 to2 carbon atoms, inclusive, R represents at whreln Y 1s from f classconslstmg of least one substituent selected from the class consisting PYY 3'PYT1dYL and 4'PYr1dY1 R1 represents at of hydrogen lower-alkyl andhalogen and R repleast one substituent selected from the classconsisting 40 resents at last one substituent seleczed from of hydrogen:lower'alkyl and halogen and R2 repre' class consisting of hydrogen,lower-alkyl, lower-alsents at least one substituent selected from theclass kenyl, trifluommethyl lower alkoxy 10Wer a1keny1 consisting ofhydrogen, lower'alkfla lower'alkenyl oxy, lower-alkylenedidxy,cycloalkyl from 4 to 7 cartrifiuorometilyl: lowepalkoxy,lower'alkenyloxy bon atoms, inclusive, halogen, andlower-alkylmereF'a1kY1?ned1QXy, cycloalkoxy from 4 to 7 carbon capto,which comprises reacting a ketone having the atoms, inclusive, halogen,and lower-alkylrnercapto; formula (b) the pharmacologically acceptableacid addition salts thereof; and (c) the quaternary ammonium salts ofthe compounds of the above formula wherein the anion of the qua- R1ternary salt is that of a pharmacologically acceptable R acid. 15. Atetrahydronaphthalene selected from the class consisting of (a)compounds having the formula Py 0H wherein R R and -C H are as definedabove, with the appropriate pyridyl lithium in the presence Q of aninert organic solvent to obtain the correspond- R ing carbinol andsubjecting the latter to dehydration.

No references cited.

WALTER A. MODANCE, Primary Examiner.

ROBERT T. BOND, Assistant Examiner.

wherein Py is selected from the class consisting of 2-pyridyl,3-pyridyl, and 4-pyridyl, R represents at CERTIFICATE OF CORRECTIONPatent No. 3 ,338 ,914 August 29, 1967 Daniel Lednicer It is herebycertified that error appears in the above numbered patent requiringcorrection and that the said Letters Patent should read as correctedbelow.

Column 1, lines 18 to 23, the formula should appear as shown belowinstead of'as in the patent:

n Zn column 2, line 22, after "maleic," insert malic,

Signed and sealed this 24th day of December 1968.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. EDWARD J.BRENNER Attesting Officer Commissioner ofPatents

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF (A) COMPOUNDS HAVINGTHE FORMULA